Substituted heterocyclic compounds

ABSTRACT

Disclosed are novel heterocyclic derivatives, useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal&#39;s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.

Priority is claimed to U.S. Provisional Patent Application Ser. No.60/440,936, filed Jan. 17, 2003, the complete disclosure of which ishereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic derivatives, inparticular piperazine and piperidine derivatives, and to their use inthe treatment of various disease states, in particular cardiovasculardiseases such as atrial and ventricular arrhythmias, intermittentclaudication, Prinzmetal's (variant) angina, stable and unstable angina,exercise induced angina, congestive heart disease, ischemia, reperfusioninjury, diabetes, myocardial infarction, and for increasing HDL levelsin plasma while lowering LDL levels. The invention also relates tomethods for their preparation, and to pharmaceutical compositionscontaining such compounds.

BACKGROUND

Certain classes of piperazine compounds are known to be useful for thetreatment of cardiovascular diseases, including arrhythmias, angina,myocardial infarction, and related diseases such as intermittentclaudication. For example, U.S. Pat. No. 4,567,264 discloses a class ofsubstituted piperazine compounds that includes a compound known asranolazine,(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide(Ranexa™), and its pharmaceutically acceptable salts, and their use inthe above disease states.

Despite the desirable properties demonstrated by ranolazine, which is avery effective cardiac therapeutic agent, believed to function as afatty acid oxidation inhibitor, there remains a need for compounds thathave similar therapeutic properties to ranolazine, but are more potentand have a longer half-life.

SUMMARY OF THE INVENTION

It is an object of this invention to provide novel substitutedpiperazine and piperidine compounds that are fatty acid oxidationinhibitors with good therapeutic half-lives. Accordingly, in a firstaspect, the invention relates to compounds of Formula I:

wherein:

-   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen, lower alkyl, or    —C(O)R;    -   in which R is —OR⁹ or —NR⁹R¹⁰, where R⁹ and R¹⁰ are hydrogen or        lower alkyl; or-   R¹ and R², R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, when taken together with    the carbon to which they are attached, represent carbonyl; or-   R¹ and R⁵, or R¹ and R⁷, or R³ and R⁵, or R³ and R⁷, when taken    together form a bridging group —(CR^(12 R) ¹³)_(n)—, in which n is    1, 2 or 3, and R¹² and R¹³ are independently hydrogen or lower    alkyl;-   with the proviso that the maximum number of carbonyl groups is 1;-   the maximum number of —C(O)NR⁹R¹⁰ groups is 1; and-   the maximum number of bridging groups is 1;-   T is oxygen, sulfur, or NR¹¹, in which R¹¹ is hydrogen or lower    alkyl;-   V is —N<, —CH<, or —NH—CH<;-   X¹ is hydrogen, optionally substituted lower alkyl, optionally    substituted cycloalkyl, optionally substituted aryl, or optionally    substituted heteroaryl;-   X² is optionally substituted aryl or optionally substituted    heteroaryl;-   Y is optionally substituted dihydroheteroaryl; and-   Z¹ and Z² are independently optionally substituted alkylene of 1–4    carbon atoms.

A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I and at least one pharmaceutically acceptableexcipient.

A third aspect of this invention relates to a method of using thecompounds of Formula I in the treatment of a disease or condition in amammal that is amenable to treatment by a fatty acid oxidationinhibitor. Such diseases include, but are not limited to, protection ofskeletal muscles against damage resulting from trauma, intermittentclaudication, shock, and cardiovascular diseases including atrial andventricular arrhythmias, Prinzmetal's (variant) angina, unstable angina,exercise induced angina, congestive heart disease, diabetes, myocardialinfarction, and for increasing HDL levels in plasma while lowering LDLlevels. The compounds of Formula I can also be used to preserve donortissue and organs used in transplants.

A fourth aspect of this invention relates to methods of preparing thecompounds of Formula I.

Of the compounds of Formula I, one preferred class includes thosecompounds in which R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are hydrogen or methyland V is —N<. A preferred group within this class includes thosecompounds in which X¹ is optionally substituted aryl and X² isoptionally substituted heteroaryl, particularly where Z¹ is methyleneand Z² is methylene or ethylene. One preferred group within the classincludes those compounds in which Y is optionally substituteddihydroheteroaryl in which the hetero atoms are chosen from nitrogen andoxygen, particularly where T is oxygen, X¹ is optionally substitutedphenyl, Y is optionally substituted dihydroisoxazolinyl, and X² isoptionally substituted benzothiazolyl. One preferred subgroup includesthose compounds in which Y is optionally substituted5-(4,5-dihydroisoxazol-3-yl). Another preferred subgroup includes thosecompounds in which Y is optionally substituted3-(4,5-dihydroisoxazolyl-5-yl).

Of the compounds of Formula I, preferred compounds include

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}propan-2-ol;

(2R)-1-{(2S)-2-methyl-4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{(3S)-3-methyl-4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{[5-(2,4,6-trimethylphenyl)(4,5-dihydroisoxazol-3-yl)]methyl}piperazinyl)propan-2-ol;

(2R)-1-((3S)-4-{[5-(2,6-dimethylphenyl)(4,5-dihydroisoxazol-3-yl)]methyl}-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}piperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(3S)-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(3S)-3-methylpiperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(2S)-2-methylpiperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(3S)-3-methylpiperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(2S)-2-methylpiperazinyl]-3-benzothiazol-5-yloxypropan-2-ol;

(2R)-1-{4-[((4S)-2-phenyl(1,3-oxazolin-4-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{(3S)-4-[((4S)-2-phenyl(1,3-oxazolin-4-yl))methyl]-3-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](2S)-2-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-{4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]piperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-{(2S)-4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]-2-methylpiperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](3S)-3-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[2-chlorophenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-(4-{[2-(4-fluorophenyl)(1,3-oxazolin-4-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-((2S)-2-methyl-4-{[3-(4-methylphenyl)(4,5-dihydroisoxazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;and

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-{[3-(4-chlorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-2-methylpiperazinyl)propan-2-ol.

More preferred compounds include:

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](2S)-2-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}propan-2-ol;

(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(3S)-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;and

(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

Definitions and General Parameters

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

-   1) an alkyl group as defined above, having from 1 to 5 substituents,    preferably 1 to 3 substituents, selected from the group consisting    of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,    acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,    azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,    carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,    alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,    aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,    hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,    —SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl and —SO₂-heteroaryl. Unless    otherwise constrained by the definition, all substituents may    optionally be further substituted by 1–3 substituents chosen from    alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,    halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R, where    R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or-   2) an alkyl group as defined above that is interrupted by 1–5 atoms    or groups independently chosen from oxygen, sulfur and —NR_(a)—,    where R_(a) is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Unless    otherwise constrained by the definition, all substituents may    optionally be further substituted by 1–3 substituents chosen from    alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,    halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R, where    R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or-   3) an alkyl group as defined above that has both from 1 to 5    substituents as defined above and is also interrupted by 1–5 atoms    or groups as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 6 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents, preferably 1 to 3 substituents, asdefined for substituted alkyl, or a lower alkyl group as defined abovethat is interrupted by 1–5 atoms as defined for substituted alkyl, or alower alkyl group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1–5 atoms asdefined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, preferably having from 1 to 20 carbonatoms, preferably 1–10 carbon atoms, more preferably 1–6 carbon atoms.This term is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1 to 6carbon atoms.

The term “substituted alkylene” refers to:

-   (1) an alkylene group as defined above having from 1 to 5    substituents selected from the group consisting of alkyl, alkenyl,    alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,    amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,    hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,    heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,    heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,    heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,    —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and    —SO₂-heteroaryl. Unless otherwise constrained by the definition, all    substituents may optionally be further substituted by 1–3    substituents chosen from alkyl, carboxy, carboxyalkyl,    aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted    amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl    and n is 0, 1 or 2; or-   (2) an alkylene group as defined above that is interrupted by 1–5    atoms or groups independently chosen from oxygen, sulfur and    NR_(a)—, where R_(a) is chosen from hydrogen, optionally substituted    alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl,    or groups selected from carbonyl, carboxyester, carboxyamide and    sulfonyl; or-   (3) an alkylene group as defined above that has both from 1 to 5    substituents as defined above and is also interrupted by 1–20 atoms    as defined above. Examples of substituted alkylenes are    chloromethylene (—CH(Cl)—), amino ethylene (—CH(NH₂)CH₂—),    methylaminoethylene (—CH(NHMe)CH₂—), 2-carboxypropylene    isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—),    ethylmethylaminoethyl    (—CH₂CH₂N(CH₃)CH₂CH₂—),1-ethoxy-2-(2-ethoxy-ethoxy)ethane    (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y—Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups areoptionally substituted alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

The term “alkylthio” refers to the group R—S—, where R is as defined foralkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 20 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having 1–6, preferably 1, double bond (vinyl).Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂), 1-propyleneor allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1–3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1–6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or prop-1-yn-3-yl, —CH₂C≡CH), and the like. In theevent that alkynyl is attached to nitrogen, the triple bond cannot bealpha to the nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1–3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or whereboth R groups are joined to form a heterocyclic group (e.g.,morpholino). Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1–3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1–3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the groups —O(O)C-alkyl, —O(O)C-cycloalkyl,—O(O)C-aryl, —O(O)C-heteroaryl, and —O(O)C-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1–3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with from 1 to 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1–3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl,heteroaryl and heterocyclyl provided that both R groups are nothydrogen, or a group —Y—Z, in which Y is optionally substituted alkyleneand Z is alkenyl, cycloalkenyl, or alkynyl, Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1–3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, andbicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example indan, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1–3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

The term “heteroaryl” refers to an aromatic group (i.e., unsaturated)comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected fromoxygen, nitrogen and sulfur within at least one ring.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1–3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a singlering (e.g., pyridyl, furyl, oxadiazolyl, oxazolyl, isoxazolyl,pyrazolyl) or multiple condensed rings (e.g., bicyclic heteroarylgroups, such as indolizinyl, benzothiazolyl, benzoxazolyl, benzothienyl,and the like). Examples of nitrogen heterocycles and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,thiazole, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “dihydroheteroaryl” refers to a heteroaryl group as definedabove in which one double bond has been saturated, and one double bondremains unsaturated. That is, a partially saturated heteroaryl group.Examples of such groups are:

in which A represents the points of attachment, which are derivativesof; 3,5-(4,5-dihydroisoxazole), 2,5-(1,3-oxazoline),3,5-(2,3-dihydro-1,2,4-oxadiazole), 3,5-(4,5-dihydro-1,2,4-oxadiazole),1,4-pyrazoline, 4,5-dihydropyridine, and the like.

Unless otherwise constrained by the definition for the dihydroheteroarylsubstituent, such dihydroheteroaryl groups can be optionally substitutedin the same manner as heteroaryl.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heterocyclyl” refers to a monoradical saturated or partiallyunsaturated group having a single ring or multiple condensed rings,having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1 to 3 substituents, selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1–3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Heterocyclicgroups can have a single ring or multiple condensed rings. Preferredheterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, andthe like.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,aryl, or heteroaryl. “Substituted sulfoxide” refers to a group —S(O)R,in which R is substituted alkyl, substituted aryl, or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl, aryl,or heteroaryl. “Substituted sulfone” refers to a group —S(O)₂R, in whichR is substituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” refersto a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

The term “compound of Formula I” is intended to encompass the compoundsof the invention as disclosed, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, and polymorphs and prodrugsof such compounds. Additionally, the compounds of the invention maypossess one or more asymmetric centers, and can be produced as a racemicmixture or as individual enantiomers or diastereoisomers. The number ofstereoisomers present in any given compound of Formula I depends uponthe number of asymmetric centers present (there are 2^(n) stereoisomerspossible where n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis,or by resolution of the compound of Formula I by conventional means. Theindividual stereoisomers (including individual enantiomers anddiastereoisomers) as well as racemic and non-racemic mixtures ofstereoisomers are encompassed within the scope of the present invention,all of which are intended to be depicted by the structures of thisspecification unless otherwise specifically indicated. “Isomers” aredifferent compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other.

The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R—S system. When the compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) which they rotate the plane of polarized light at thewavelength of the sodium D line.

The term “therapeutically effective amount” refers to that amount of acompound of Formula I that is sufficient to effect treatment, as definedbelow, when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Fatty acid oxidation inhibitors” refers to compounds that suppress ATPproduction from the oxidation of fatty acids and consequently stimulateATP production from the oxidation of glucose and lactate. In the heart,most of the ATP production is acquired through the metabolism of fattyacids. The metabolism of glucose and lactate provides a lesserproportion of ATP. However, the generation of ATP from fatty acids isless efficient with respect to oxygen consumption than the generation ofATP from the oxidation of glucose and lactate. Thus, the use of fattyacid oxidation inhibitors results in more energy production per moleculeof oxygen consumed, allowing the heart to be energized more efficiently.Fatty acid oxidation inhibitors are especially useful, therefore, fortreating an ischemic environment in which oxygen levels are reduced.

Nomenclature

The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen, T is oxygen, X¹ is(4-trifluoromethyl)phenyl, X² is 2-methylbenzothiazol-5-yl, Y is5-(4,5-dihydroisoxazol-3-yl), and Z¹ and Z² are methylene:

which is named:

-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;    or alternatively;-   (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol.

Synthesis of the Compounds of Formula I

One method of preparing the compounds of Formula I is shown in ReactionScheme I.

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, T, X¹, X², Y, and Z¹, are asdefined in the Summary of the Invention, Z² is methylene, Hal ishalogen, and t-but is tertiary butyl.Starting Materials

The compounds of formula (1), (2), and (3) are either commerciallyavailable or can be made by conventional methods well known to those ofordinary skill in the art. For example, the precursor to a compound offormula (4) where R¹ and R⁵ when taken together represent a bridgingmethylene group, i.e.;

is commercially available [(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane],or can be made by a procedure disclosed in J. Org. Chem., 1990, 55,1684–7. Similarly, the precursor to a compound of formula (4) where R¹and R⁵ when taken together represent a bridging ethylene group, and theprecursor to a compound of formula (4) where R¹ and R⁷ when takentogether represent a bridging ethylene group, can be made by publishedprocedures found in J. Med. Chem., 1974, 17, 481–7. The precursor to acompound of formula (4) in which R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ arehydrogen and R⁸ is —C(O)NH₂ is prepared from piperazine-2-carboxamide, acommercially available compound.Step 1—Preparation of Formula (3)

The compound of formula (3) is prepared conventionally by reaction of acompound of formula (1), for example 5-hydroxy-2-methylbenzothiazole,with an epoxide of formula (2), which may be racemic or chiral. Ingeneral, the two compounds are mixed in an inert solvent, preferably aketone, for example acetone, and a tertiary organic base or an inorganicbase, preferably potassium carbonate, at a temperature of about reflux,for about 8–48 hours, preferably overnight. When the reaction issubstantially complete, the product of formula (3) is isolated byconventional means, for example by filtration, removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel. Alternatively, after filtration the product can becrystallized from the filtrate.

Step 2—Preparation of Formula (5)

The compound of formula (3) is then reacted with a protected piperazineof formula (4). In general, the two compounds are mixed in an inertsolvent, preferably a halogenated solvent, for example methylenechloride, optionally in the presence of a catalyst, for exampleytterbium (III) trifluoromethanesulfonate. In the presence of a catalystthe reaction is conducted at about 0–30° C., preferably at about roomtemperature, for about 8–48 hours, preferably overnight. In the absenceof a catalyst, the mixture is refluxed for a similar period of time inethanol in the presence of triethylamine. When the reaction issubstantially complete, the product of formula (5) is isolated byconventional means, for example by removal of the solvent under reducedpressure, followed by chromatography of the residue on silica gel.

Step 3—Preparation of Formula (6)

The compound of formula (5) is then deprotected by hydrolyzing thet-butyl ester. In general, the compound of formula (5) is dissolved in amixture of an inert solvent, preferably a halogenated solvent, forexample methylene chloride, and a strong acid, for exampletrifluoroacetic acid. The reaction is conducted at about 0–30° C.,preferably at about room temperature, for about 8–48 hours, preferablyovernight. When the reaction is substantially complete, the product offormula (6) is isolated by conventional means, for example by adding abase to remove excess acid, and removal of the solvent under reducedpressure.

Step 4—Preparation of a Compound of Formula I

The compound of formula (6) is then reacted with a compound of formula(7) (X¹—Y—Z¹-Hal), for example3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole.Examples of such compounds are3-(4-trifluoromethylphenyl)-5-chloromethyl-2,3 dihydro-1,2,4-oxadiazole,5-bromomethyl-4-methyl-2-phenyl-1,2,3-triazoline, or4-chloromethyl-2-(4-trifluoromethylphenyl)-1,3-thiazoline, and the like.Such compounds are either commercially available, prepared by means wellknown in the art (see, for example, see J. Med. Chem., 1996, 39,237–243) or prepared as shown herein. In general, the two compounds aremixed in an inert solvent, preferably a protic solvent, for exampleethanol, in the presence of an inorganic or tertiary organic base,preferably triethylamine. The reaction is conducted at about 30–100° C.,preferably at about reflux, for about 8–48 hours, preferably overnight.When the reaction is substantially complete, the product of Formula I isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by chromatography.

A modified procedure is preferred for preparing compounds of Formula Iin which R⁸ is lower alkyl and R¹–R⁷ are hydrogen. An example where R⁸is methyl is shown in Reaction Scheme IA.

Step 1—Preparation of Formula (6)

The compound of formula (3) is reacted with 2-methylpiperazine. Ingeneral, the two compounds are mixed in a protic solvent, for exampleethanol. The reaction is conducted at about 5–100° C., preferably atabout 80° C., for about 1–12 hours, preferably about 5 hours. When thereaction is substantially complete, the product of formula (6) isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel.

The compound of formula (6) is then reacted with a compound of formula(7) as described above in Reaction Scheme I, step 4, to provide acompound of Formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ arehydrogen and R⁸ is methyl.

A different procedure is preferred for preparing compounds of Formula Iin which R⁴ is lower alkyl and R¹–R³ and R⁵–R⁸ are hydrogen. An examplewhere R⁴ is methyl is shown in Reaction Scheme IB.

Step 1—Preparation of Formula (7a)

The compound of formula (7) is reacted with 2-methylpiperazine. Ingeneral, the two compounds are mixed in an inert solvent, preferably aprotic solvent, for example ethanol, in the presence of an inorganic ortertiary organic base, preferably triethylamine. The reaction isconducted at about 30–100° C., preferably at about 60° C., for about2–12 hours, preferably about 8 hours. When the reaction is substantiallycomplete, the product of formula (7a) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography.

The compound of formula (7a) is then reacted with an epoxide of formula(3) as described in Reaction Scheme I, step 2, to provide a compound ofFormula I in which R¹, R², R³, R⁵, R⁶, R⁷ and R⁸are hydrogen and R⁴ ismethyl.

A preparation of intermediates for synthesizing compounds of Formula Iin which Y is 2-substituted-(1,3-oxazolin-5-yl) is shown in ReactionScheme II.

Step 1—Preparation of a Compound of Formula (8)

A carboxylic acid of formula X¹C(O)OH, is reacted with commerciallyavailable methyl 2-amino-3-hydroxypropanoate (7). In general, the twocompounds are mixed in an inert solvent, for example dichloromethane, inthe presence of an inorganic or tertiary organic base, preferablytriethylamine. The reaction is conducted at about room temperatureovernight. When the reaction is substantially complete, the product offormula (8) is isolated by conventional means, for example by removal ofthe solvent under reduced pressure, followed by chromatography.

Step 2—Preparation of a Compound of Formula (9)

The compound of formula (8) is then cyclized by reaction withdiisopropylazodicarboxylate, or the like, in the presence oftriphenylphosphine, to provide a 4-carbomethoxy-1,3-oxazoline of formula(9). The reaction is conducted in an inert solvent, for exampletetrahydrofuran, at about room temperature for 1–5 days. When thereaction is substantially complete, the product of formula (9) isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by chromatography.

Step 3—Preparation of a Compound of Formula (10)

The carbomethoxy group of the compound of formula (9) is then reduced byconventional means to a hydroxymethyl group, to provide a compound offormula (10), for example by reduction with lithium aluminum hydride inan ethereal solvent, for example tetrahydrofuran, at about 0° C. Whenthe reaction is substantially complete, the product of formula (10) isisolated by conventional means, for example by quenching excess reducingagent with water, extraction with an inert solvent, for example ethylacetate, removal of the solvent under reduced pressure, followed bychromatography.

The hydroxymethyl compound of formula (10) thus produced is converted toa compound of formula (10a), in which LG is a leaving group, by reactionwith a reagent capable of converting the hydroxy group to a leavinggroup, for example by conversion to a chloride or bromide byconventional means, or by reaction with an alkyl or aryl sulfonylchloride, for example reaction with methanesulfonyl chloride, to form amesylate. The mesylate is then reacted with a compound of formula (6) inthe same manner as shown in Reaction Scheme I to provide a compound ofFormula I in which Y is 2-substituted-(1,3-oxazolin-5-yl).

Intermediates for the preparation of compounds of Formula I in which Yis 5-substituted-(4,5-dihydroisoxazol-3-yl) are made as shown inReaction Scheme III.

Step 1—Preparation of a Compound of Formula (13)

A vinyl derivative of formula (11) is reacted with ethyl2-chloro-2-(hydroxyamino)acetate (12) in an inert solvent, for exampletetrahydrofuran, in the presence of a tertiary base, for exampletriethylamine, for about 30 minutes to 4 hours. When the reaction issubstantially complete, the product of formula (13) is isolated byconventional means.

Step 2—Preparation of a Compound of Formula (14)

The carboxyethyl group of the compound of formula (13) is then reducedby conventional means to a hydroxymethyl group, to provide a compound offormula (14), for example by reduction with sodium borohydride in aprotic solvent, for example ethanol, at about 0° C., for about 2–8hours. When the reaction is substantially complete, the product offormula (14) is isolated by conventional means, for example by quenchingexcess reducing agent with water, extraction with an inert solvent, forexample ethyl acetate, removal of the solvent under reduced pressure,followed by chromatography.

The hydroxymethyl of formula (14) may then be converted to achloromethyl group by conventional means, for example thionyl chloride.or alternatively the hydroxy group may be converted to a mesyl group(leaving group) by reaction with methanesulfonyl chloride. The compoundthus formed is then reacted with a piperazine derivative of formula (6)in the same manner as shown in Reaction Scheme I to provide a compoundof Formula I in which Y is 5-substituted-(4,5-dihydroisoxazol-3-yl).

A method for preparing compounds of Formula I in which Y is3-substituted-(4,5-dihydroisoxazol-3-yl is shown in Reaction Scheme IV.

Step 1—Preparation of a Compound of Formula (15)

A compound of formula (6) is reacted with a compound of formulaHC═C—Z¹Br (for example, allyl bromide). In general, the two compoundsare mixed in an inert solvent, for example acetone, in the presence ofan inorganic or tertiary organic base, preferably potassium carbonate.The reaction is conducted at about 30–100° C., preferably at aboutreflux, for about 1–10 hours, preferably about 5 hours. When thereaction is substantially complete, the product of formula (15) isisolated and purified by conventional means, for example by removal ofthe solvent under reduced pressure, followed by preparativechromatography.

Step 2—Preparation of a Compound of Formula I

The compound of formula (15) is then reacted with a nitrile oxide,prepared by oxidation of an oxime of formula X¹—CH═NOH. The oxidation iscarried out conventionally, for example by treatment of the oxime withan oxidizing agent such as aqueous sodium hypochlorite indichloromethane. To the nitrile oxide thus prepared, the compound offormula (15) is added in an inert solvent, for example dichloromethane,in the presence of an inorganic or tertiary organic base, preferablytriethylamine. The reaction is carried out in a sealed vessel at anelevated temperature, preferably subjecting the sealed vessel tomicrowave at about 110° C. for about 4 minutes. When the reaction issubstantially complete, the product of Formula I is isolated andpurified by conventional means, for example by removal of the solventunder reduced pressure, followed by preparative chromatography. Thisprovides a compound of Formula I in which Y is3-substituted-(4,5-dihydroisoxazol-5-yl).

An alternative method for preparing compounds of Formula I in which Y is3-substituted-(4,5-dihydroisoxazol-5-yl) is shown in Reaction Scheme V.

Step 1—Preparation of a Compound of Formula (17)

An oxime of formula (16), which is commercially available or prepared bymeans well known in the art, is reacted with a halogenating agent, forexample N-chlorosuccinimide. In general, the two compounds are mixed inan inert solvent, for example dichloromethane, and reacted at about0–30° C., preferably at about room temperature, for about 1–10 hours,preferably about 3 hours. When the reaction is substantially complete,the product of formula (17) is typically used in the next reaction withno purification.

Step 2—Preparation of a Compound of Formula (18)

The compound of formula (17) is then reacted with a vinylic ester, forexample vinyl acetate. The reaction is carried out in an inert solvent,for example dichloromethane, in the presence of an inorganic or tertiaryorganic base, for example triethylamine. The reaction is carried out atabout 0–30° C., preferably at about room temperature, for about 10–48hours, preferably overnight. When the reaction is substantiallycomplete, the product of formula (18) is isolated and purified byconventional means, for example by removal of the solvent under reducedpressure, followed by preparative chromatography.

Step 3—Preparation of a Compound of Formula (14a)

The compound of formula (18) is then hydrolyzed to the hydroxymethylcompound of formula (14a) by reaction with a strong base, for examplesodium hydroxide. The reaction is carried out in a protic solvent, forexample ethanol-water mixture, at a temperature of about 0–30° C.,preferably at about room temperature, for about 1–6 hours, preferablyfor about 3 hours. When the reaction is substantially complete, theresulting solution is neutralized, and the product of formula (14a) isisolated and purified by conventional means.

The hydroxy group of the compound of formula (14a) is then converted toa leaving group, for example a chloro or mesyl group, by conventionalmeans, as shown previously. The resulting halomethyl or mesylmethylcompound is then reacted with a piperazine derivative of formula (6) inthe same manner as shown in Reaction Scheme I to provide a compound ofFormula I in which Y is 3-substituted-(4,5-dihydroisoxazol-5-yl).

An example of a method for preparing compounds of Formula I in which X¹is optionally substituted aryl or optionally substituted heteroaryl andY is optically active is shown in Reaction Scheme VI.

Step 1—Preparation of Compound of Formula (20)

The compound of formula (20) is prepared by reacting a compound offormula (19) with hydroxylamine hydrochloride (NH₂OH.HCl). In general,the two compounds are mixed in a protic solvent, for example methanol,in the presence of an inorganic or tertiary organic base, preferablypotassium carbonate. The reaction is conducted at about 30–100° C.,preferably at about 60–70° C., for about 2–20 hours, preferably about 10hours. When the reaction is substantially complete, the product offormula (20) is isolated and purified by conventional means, for exampleby filtration and removal of solvent under reduced pressure, followed bypreparative chromatography.

Step 2—Preparation of Compound of Formula (21)

The compound of formula (20) is reacted with a halogenating agent,preferably N-chlorosuccinimide (NCS) in a polar inert solvent,preferably dimethylformamide. In general, the reaction is conductedinitially at a low temperature, preferably about 0° C., and then atabout 30–70° C. for about 1–10 hours, preferably 3 hours. When thereaction is substantially complete, the product of formula (21) isisolated and purified by conventional means, for example by removal ofsolvent under reduced pressure, followed by preparative chromatographyof the residue.

Step 3—Preparation of Compound of Formula (22)

A solution of allyl alcohol in an aprotic solvent is reacted withdiethylzinc at a low temperature, preferably about 0° C. The resultingmixture is then reacted with a chiral tartrate, for example(+)diisopropyl tartrate (+) or (−)diisopropyl tartrate for 1–10 hours,preferably 2 hours, after which another portion of diethylzinc is added.The compound of formula (21) is then added to the mixture thus produced,and reacted at 0° C. for another 1–10 hours, preferably about 2 hours.When the reaction is substantially complete, the product of formula (22)is isolated and purified by conventional means, for example byconventional workup and removal of solvent under reduced pressure,followed by preparative chromatography of the residue.

The hydroxy group of the compound of formula (22) is then converted to aleaving group, for example a chloro or mesyl group, by conventionalmeans, as shown previously. The resulting halomethyl or mesylmethylcompound is then reacted with a piperazine derivative of formula (6) inthe same manner as shown in Reaction Scheme I to provide a compound ofFormula I in which X¹ is optionally substituted aryl or optionallysubstituted heteroaryl and Y is optically active.

General Utility

The compounds of Formula I are effective in the treatment of conditionsknown to respond to administration of fatty acid oxidation inhibitors,including protection of skeletal muscles against damage resulting fromtrauma, intermittent claudication, shock, and cardiovascular diseasesincluding atrial and ventricular arrhythmias, Prinzmetal's (variant)angina, stable angina, ischemia and reperfusion injury in cardiac,kidney, liver and the brain, exercise induced angina, congestive heartdisease, and myocardial infarction. Fatty acid oxidation inhibitors haverecently been shown to modify glucose levels in diabetic patients, thusproviding a novel method of treating diabetes, and in particular providean effective treatment of angina in diabetics. Fatty acid oxidationinhibitors have also been shown to raise plasma HDL levels and lower LDLlevels in mammals, thus providing a method for treating coronary arterydisease. The compounds of Formula I can also be used to preserve donortissue and organs used in transplants, and may be coadministered withthrombolytics, anticoagulants, and other agents.

Testing

Activity testing is conducted as described in those patents and patentapplications referenced above, and in the Examples below, and by methodsapparent to one skilled in the art.

Pharmaceutical Compositions

The compounds of Formula I are usually administered in the form ofpharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed.(G. S. Banker & C. T. Rhodes, Eds.).

Administration

The compounds of Formula I may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parental, particularly by injection. Theforms in which the novel compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof Formula I in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Compounds of Formula I may be impregnated into a stent by diffusion, forexample, or coated onto the stent such as in a gel form, for example,using procedures known to one of skill in the art in light of thepresent disclosure. Oral administration is another route foradministration of the compounds of Formula I. Administration may be viacapsule or enteric coated tablets, or the like. In making thepharmaceutical compositions that include at least one compound ofFormula I, the active ingredient is usually diluted by an excipientand/or enclosed within such a carrier that can be in the form of acapsule, sachet, paper or other container. When the excipient serves asa diluent, it can be in the form of a solid, semi-solid, or liquidmaterial (as above), which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, sterile injectablesolutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds of Formula I are effective over a wide dosage range and aregenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 1 mgto 2 g of a compound of Formula I, and for parenteral administration,preferably from 0.1 to 700 mg of a compound of Formula I. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Preparation of a Compound of Formula (3)

A. Preparation of a Compound of Formula (3) in which T is Oxygen, X² is2-Methylbenzothiazol-5-yl, and Z² is Methylene

A mixture of 2-methylbenzothiazol-5-ol, a compound of formula (1) (6.0g, 36 mmol), (S)-(+)-epichlorohydrin, a compound of formula (2) (20 ml,182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml),was heated to reflux and allowed to stir overnight. The solution wasallowed to cool and filtered through Celite 512. The filtrate wasevaporated (in vacuo), to yield an oil. The oil was chromatographed onsilica gel, eluting with 20% ethyl acetate/hexanes, to yield5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole as a white solid (6.2g, 28 mmol).

B. Preparation of a Compound of Formula (3) in which T is Oxygen, X² is2-Phenylbenzothiazol-5-yl, and Z² is Methylene

Similarly, following the procedure of 1A above, but replacing2-methylbenzothiazol-5-ol with 2-phenylbenzoxazol-5-ol, a compound offormula (3) where X² is 2-phenylbenzoxazol-5-yl, T is oxygen, and Z² ismethylene was prepared, namely5-[((2R)oxiran-2-yl)methoxy]-2-phenylbenzoxazole.

Similarly, the following compounds of formula (3) were prepared:

-   4-[((2R)oxiran-2-yl)methoxy]-1-methoxybenzene; and-   4-[((2R)oxiran-2-yl)methoxy]-2-fluorobenzene.    C. Preparation of a Compound of Formula (3), Varying T, X², and Z²

Similarly, following the procedure of 1A above, but optionally replacing2-methylbenzothiazol-5-ol with other compounds of formula (1), andoptionally replacing (S)-(+)-epichlorohydrin with other appropriatelysubstituted compounds of formula (2), the following compounds of formula(3) are prepared as R, S isomers, or racemic mixtures.

-   5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole;-   5-[((2RS)oxiran-2-yl)methoxy]-2-methylbenzothiazole-   1-[2-((2S)oxiran-2-yl)ethoxy]-2-methoxybenzene-   4-[((2R)oxiran-2-yl)methoxy]-2-chlorobenzene;-   5-[2-((2S)oxiran-2-yl)ethoxy]-2-methylbenzothiazole-   4-[(oxiran-2-yl)ethoxy]-2-fluorobenzene;-   4-[(oxiran-2-yl)ethoxy]-4-methoxybenzene;-   8-fluoro-1-(oxiran-2-ylmethoxy)naphthalene;-   1-fluoro-2-(oxiran-2-ylmethoxy)naphthalene;-   2-ethyl-4-(oxiran-2-yl methoxy)thiazole;-   4-methyl-2-(oxiran-2-yl methoxy)imidazole;-   2-methyl-5-(oxiran-2-yl methoxy)benzimidazole; and-   2-phenyl-5-(oxiran-2-yl methoxy)benzimidazole.    D. Preparation of a Compound of Formula (3), Varying T, X², and Z²

Similarly, following the procedure of 1A above, but optionally replacing2-methylbenzothiazol-5-ol with other compounds of formula (1), andoptionally replacing (S)-(+)-epichlorohydrin with other appropriatelysubstituted compounds of formula (2), other compounds of formula (3) areprepared.

EXAMPLE 2 Preparation of a Compound of Formula (5)

A. Preparation of a Compound of Formula (5) in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X² is2-Methylbenzothiazol-5-yl, and Z² is Methylene

To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole, acompound of formula (3) (6.2 g, 28 mmol), and tert-butyl1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), inmethylene chloride (200 ml), was added ytterbium (111)trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution wasallowed to stir at room temperature overnight. The solvent wasevaporated (in vacuo), to yield a semi-solid, which was chromatographedon silica gel, eluting with 5% methanol/methylene chloride, to yieldtert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylateas a clear oil (9.5 g, 23 mmol).

B. Preparation of a Compound of Formula (5) in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X² is 2-Phenylbenzoxazol-5-yl,and Z² is Methylene

Similarly, following the procedure of 2A above, but replacing5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole with other compoundsof formula (3), the following compounds of formula (5) were prepared:

-   tert-butyl    4-[(2R)-2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]-piperazinecarboxylate;-   tert-butyl    4-[(2R)-2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazinecarboxylate;    and-   tert-butyl    4-[(2R)-2-hydroxy-3-(2-fluorophenoxy)propyl]piperazinecarboxylate.    C. Alternative Preparation of a Compound of Formula (5) in which R¹,    R², R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, R³ is Methyl, T is Oxygen,    X² is 2-Phenylbenzoxazol-5-yl, and Z² is Methylene

To a solution of 5-(((R)-oxiran-2-yl)methoxy)-2-methylbenzo[d]thiazole(3.24 g, 14.6 mmol) in tert-amyl alcohol (50 ml) was added(S)-tert-butyl 3-methylpiperazine-1-carboxylate (2.67 g, 13.3 mmol). Theresulting mixture was stirred at 100° C. for 16 hours. It was thencooled, concentrated, and purified by chromatography (1:20 MeOH:CH₂Cl₂)to yield tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](3S)-3-methylpiperazinecarboxylate(4.8 g, 11.4 mmol).

D. Preparation of a Compound of Formula (5), Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷ R⁸, T, X², and Z²

Similarly, following the procedure of 2A or 2C above, but optionallyreplacing 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole with othercompounds of formula (3), and optionally replacing tert-butyl1-piperazinecarboxylate with other compounds of formula (4), thefollowing compounds of formula (5) are prepared as racemates or singleenantiomers:

-   tert-butyl    4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazinecarboxylate;-   tert-butyl    4-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperazinecarboxylate;-   tert-butyl    4-[2-hydroxy-3-(2-fluorophenoxy)propyl]piperazinecarboxylate;-   tert-butyl    4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazinecarboxylate;-   4-[2-hydroxy-3-(8-fluoronaphth-1-yloxy)propyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   4-[2-hydroxy-3-(1-fluoronaphth-2-yloxy)propyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   4-[2-hydroxy-3-(2-ethylthiazol-4-yloxy)propyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   4-[2-hydroxy-3-(4-methylimidazol-4-yloxy)propyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   4-[2-hydroxy-3-(2-methylbenzmiidazol-5-yloxy)propyl]-piperazine-1-carboxylic    acid tert-butyl ester; and-   4-[2-hydroxy-3-(2-phenylbenzimidazo-5-yloxy)propyl]-piperazine-1-carboxylic    acid tert-butyl ester.    E. Preparation of a Compound of Formula (5), Varying R¹, R², R³, R⁴,    R⁵, R⁶, R⁷ R⁸, T, X² and Z²

Similarly, following the procedure of 2A or 2C above, but optionallyreplacing 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole with othercompounds of formula (3), and optionally replacing tert-butyl1-piperazinecarboxylate with other compounds of formula (4), othercompounds of formula (5) are prepared as racemates or singleenantiomers.

EXAMPLE 3 Preparation of a Compound of Formula (6)

A. Preparation of a Compound of Formula (6) in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X² is2-Methylbenzothiazol-5-yl, and Z² is Methylene

A solution of tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate,a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroaceticacid/methylene chloride (20 ml) was allowed to stir at room temperatureovernight. The solvent was evaporated (in vacuo) to yield an oil. Theoil was diluted with acetone (20 ml) and solid potassium carbonate wasadded until the foaming stopped. The resulting mixture was allowed tostir overnight. The solution was filtered through Celite 512, and thefiltrate was evaporated (in vacuo), to yield an oil. The oil was placedunder high vacuum overnight, to yield(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as aclear viscous oil (3.4 g. 6.3 mmol).

B. Preparation of a Compound of Formula (6) in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X² is 2-Phenylbenzoxazol-5-yl,and Z² is Methylene

Similarly, following the procedure of 3A above, but replacing tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylatewith tert-butyl4-[(2R)-2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]piperazinecarboxylate,the compound of formula (6) where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen, X² is 2-phenylbenzoxazol-5-yl, T is oxygen, and Z² ismethylene was prepared, namely(2R)-1-(2-phenylbenzoxazol-5-yloxy)-3-piperazinylpropan-2-ol.

Similarly, the following compounds of formula (6) were prepared:

-   (2R)-1-((2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-(2-methoxyphenoxy)-3-piperazinylpropan-2-ol; and-   (2R)-1-(2-fluorophenoxy)-3-piperazinylpropan-2-ol.    C. Preparation of a Compound of Formula (6), varying R¹, R², R³, R⁴,    R⁵, R⁶, R⁷ R⁸, T, X², and Z²

Similarly, following the procedure of 3A above, but replacing tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylatewith other compounds of formula (5), the following compounds of formula(6) are prepared as racemates or single enantiomers:

-   4-(2-methoxyphenoxy)-1-piperazinylbutan-2-ol;-   4-(2-chlorophenoxy)-1-piperazinylbutan-2-ol;-   4-(2-methylbenzothiazol-5-yloxy)-1-piperazinylbutan-2-ol-   4-(2-fluorophenoxy)-1-piperazinylpropan-2-ol;-   4-(4-methoxyphenoxy)-1-piperazinylpropan-2-ol;-   1-(8-fluoronaphthyloxy)-3-piperazinylpropan-2-ol;-   1-(1-fluoronaphth-2-yloxy)-3-piperazinylpropan-2-ol;-   1-(2-ethylthiazol-4-yloxy)-3-piperazinylpropan-2-ol;-   1-(4-methylimidazol-4-yloxy)-3-piperazinylpropan-2-ol;-   1-(2-methylbenzimidazol-5-yloxy)-3-piperazinylpropan-2-ol; and-   1-(2-phenylbenzimidazol-5-yloxy)-3-piperazin-1-yl-propan-2-ol.    D. Preparation of a Compound of Formula (6), varying R¹, R², R³, R⁴,    R⁵, R⁶, R⁷ R⁸, T, X², and Z²

Similarly, following the procedure of 3A above, but replacing tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylatewith other compounds of formula (5), other compounds of formula (6) areprepared as racemates or single enantiomers.

EXAMPLE 4 Preparation of a Compound of Formula (8)

A. Preparation of a Compound of Formula (8) in which X¹ is4-Fluorophenyl

To 50 ml of tetrahydrofuran was added 4-fluorobenzoic acid (3.64 g, 26mmol), L-serine methyl ester hydrochloride (2 g, 13 mmol),1-hydroxybenzotriazole hydrate (4 g, 26 mmol),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(9.9 g, 26 mmol), triethylamine (3.5 ml, 26 mmol) anddimethylaminopyridine (20 mg, 0.16 mmol). The reaction was stirred for24 hours at room temperature. Solvent was removed under reducedpressure, and the residue dissolved in 150 ml of ethyl acetate. Theorganic solution was washed in a separatory funnel in the followingmanner: 3×100 ml 10% aqueous citric acid, 3×100 ml saturated sodiumbicarbonate, 3×100 ml water, 1×75 ml saturate sodium chloride solution.The organic layer was concentrated and purified using a Flash40 column(1:2 EtOAc:Hexane, 20 psi) to yield 3 grams of methyl2-[(4-fluorophenyl)carbonylamino]-3-hydroxypropanoate.

B. Preparation of a Compound of Formula (8), Varying X¹

Similarly, following the procedure of 4A above, but replacing4-fluorobenzoic acid with other compounds of formula X¹—CO(O)H, othercompounds of formula (8) are prepared as racemates or singleenantiomers.

EXAMPLE 5 Preparation of a Compound of Formula (9)

A. Preparation of a Compound of Formula (9) in which X¹ is4-Fluorophenyl

To 25 ml tetrahydrofuran was added methyl2-[(4-fluorophenyl)carbonylamino]-3-hydroxypropanoate (0.750 g, 3 mmol),triphenylphosphine (1.0 g, 4.5 mmol) and diisopropylazodicarboxylate(0.800 g, 4.5 mmol). The reaction was stirred at room temperature undernitrogen until SM was shown to be consumed (TLC, 1:1 EthylAcetate:Hexane). The reaction mixture was concentrated under reducedpressure and purified using a Flash 40 Column (1:1 EtOAc:Hexane, 20 psi)to yield 1 g of methyl 2-(4-fluorophenyl)-1,3-oxazoline-4-carboxylate(M+1=224.2).

B. Preparation of a Compound of Formula (9), Varying X¹

Similarly, following the procedure of 5A above, but replacing methyl2-[(4-fluorophenyl)carbonylamino]-3-hydroxypropanoate with othercompounds of formula (8), other compounds of formula (9) are prepared asracemates or single enantiomers.

EXAMPLE 6 Preparation of a Compound of Formula (10)

A. Preparation of a Compound of Formula (10) in which X¹ is4-Fluorophenyl

Methyl 2-(4-fluorophenyl)-1,3-oxazoline-4-carboxylate (1.0 g, 4.5 mmol)was dissolved in 30 ml of absolute ethanol. To this solution was addedlithium chloride (0.380 g, 9.0 mmol) and sodium borohydride (0.342 g,9.0 mmol). The reaction was stirred at room temperature until startingmaterial was consumed (TLC, 15:1 dichloromethane:methanol). Ethanol wasremoved under reduced pressure and replaced with 35 ml of water. Theaqueous solution was acidified to about pH 2 with concentrated HCl, andthe acidic solution extracted with ethyl acetate (3×50 ml). Theresulting organic layer was washed with water (3×50 ml) and dried withsodium sulfate. The organic layer was concentrated under reducedpressure, and the residue purified using column chromatography (3% MeOHin DCM) to yield [2-(4-fluorophenyl)-1,3-oxazolin-4-yl]methan-1-ol (600mg, M+1=196.1).

B. Preparation of a Compound of Formula (10), Varying X¹

Similarly, following the procedure of 6A above, but replacing methyl2-(4-fluorophenyl)-1,3-oxazoline-4-carboxylate with other compounds offormula (9), other compounds of formula (10) are prepared as racematesor single enantiomers.

EXAMPLE 7 Preparation of a Compound of Formula (10a)

A. Preparation of a Compound of Formula (10a) in which X¹ is4-Fluorophenyl and LG is Bromo

To a solution of [2-(4-fluorophenyl)-1,3-oxazolin-4-yl]methan-1-ol (500mg, 2.5 mmol) in pyridine (30 ml) cooled to 0° under inert conditionswas added triphenylphosphine (1.3 g, 5.0 mmol). Carbon tetrabromide (817mg, 2.5 mmol) was added in 4 fractions (˜200 mg each). The reactionmixture was stirred at zero degrees until all starting material wasconsumed, as shown by TLC (1:1 EtOAc:Hexanes). Methanol (˜5 ml) wasadded to quench the reaction. The solution was evaporated under reducedpressure, and the residue was purified using column chromatography (1:1EtOAc:Hexanes) to yield compound4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazoline (300 mg, HNMR).

B. Preparation of a Compound of Formula (10a), Varying X¹

Similarly, following the procedure of 7A above, but replacing[2-(4-fluorophenyl)-1,3-oxazolin-4-yl]methan-1-ol with other compoundsof formula (10), other compounds of formula (10a) are prepared asracemates or single enantiomers.

EXAMPLE 8 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X¹—Y— is2-(4-Fluorophenyl)-4,5-dihydro-1,3-oxazolin-4-yl, X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

To a solution of 4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazoline (80mg, 0.31 mmol) in dimethylformamide (2 ml) was added(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (180 mg,0.47 mmol) and potassium carbonate (250 mg, 1.92 mmol). The mixture washeated to 75 degrees and stirred for 12 hours. The reaction was thenconcentrated under reduced pressure and the residue purified usingpreparative chromatography (10:1 dichloromethane:methanol) to yield(2R)-3-(4-{[2-(4-fluorophenyl)(4,5-dihydro-1,3-oxazolin-4-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol(6 mg, M+1=485.05).

B. Preparation of a Compound of Formula I, Varying X¹

Similarly, following the procedure of 8A above, but optionally replacing4-(bromomethyl)-2-(4-fluorophenyl)-4,5-dihydro-1,3-oxazoline with othercompounds of formula (10a), and optionally replacing(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol withother compounds of formula (6), the following compounds of Formula Iwere prepared:

(2R)-1-{4-[((4S)-2-phenyl(1,3-oxazolin-4-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-{4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]piperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;and

(2R)-3-(4-{[2-(4-fluorophenyl)(1,3-oxazolin-4-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

C. Preparation of a Compound of Formula I, Varying X¹

Similarly, following the procedure of 8A above, but optionally replacing4-(bromomethyl)-2-(4-fluorophenyl)-4,5-dihydro-1,3-oxazoline with othercompounds of formula (10a), and optionally replacing(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol withother compounds of formula (6), other compounds of Formula I areprepared as racemates or single enantiomers.

EXAMPLE 9 Preparation of a Compound of Formula (13)

A. Preparation of a Compound of Formula (13) in which X¹ is4-Trifluorophenyl

To a stirred mixture of 2-chloro-2-hydroxyiminoacetic acid ethyl ester(2.11 g, 13.52 mmol) and 4-trifluoromethystyrene (2.0 g, 11.27 mmol) inanhydrous tetrahydrofuran (15 ml) was added dropwise a solution oftriethylamine (3.0 ml, 21.52 mmol) in tetrahydrofuran (5 ml) at roomtemperature. The resulting reaction mixture was stirred at an atmosphereof nitrogen for 16 hours, filtered, partitioned between water and ethylacetate (2×50 ml), washed with saturated aqueous sodium bicarbonate, 30%aqueous ammonium chloride, brine, dried over sodium sulfate, andconcentrated to afford a pale yellow solid, which was purified bychromatography (2:8 EtOAc:Hexane) to afford ethyl5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate (2.86g, M+1=288.2)

B. Preparation of a Compound of Formula (13), Varying X¹

Similarly, following the procedure of 9A above, but replacing4-trifluoromethystyrene with other compounds of formula (11), thefollowing compounds of formula (13) were prepared:

-   ethyl    5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate;-   ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate;-   ethyl 5-(2,4,6-trimethylphenyl)-4,5-dihydroisoxazole-3-carboxylate;-   ethyl 5-(2,6-dimethylphenyl)-4,5-dihydroisoxazole-3-carboxylate; and-   ethyl 5-(2-chlorophenyl)-4,5-dihydroisoxazole-3-carboxylate.    C. Preparation of a Compound of Formula (13), Varying X¹

Similarly, following the procedure of 9A above, but replacing4-trifluoromethystyrene with other compounds of formula (11), othercompounds of formula (13) are prepared.

EXAMPLE 10 Preparation of a Compound of Formula (14)

A. Preparation of a Compound of Formula (14) in which X¹ is4-Trifluorophenyl

To a stirred mixture of sodium borohydride (378 mg, 10.0 mmol) inethanol (20 ml) was added slowly a solution of ethyl5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate (1.6 g,5.75 mmol) in ethanol (10 mL). The resulting reaction mixture wasstirred under an atmosphere of nitrogen for 8 hours. Ethanol was removedunder reduced pressure and water (20 ml) added. The aqueous mixture wasacidified to about pH 3 with concentrated HCl, and the acidic solutionextracted with ethyl acetate (3×20 ml). The resulting organic phase waswashed with saturated aqueous sodium bicarbonate (20 ml), 30% aqueousammonium chloride(20 ml), brine, dried over sodium-sulfate,concentrated, and purified using chromatography (3% MeOH in CH₂Cl₂) toafford (5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol(1.1 g, M+1=246.1).

B. Preparation of a Compound of Formula (14), Varying X¹

Similarly, following the procedure of 10A above, but replacing ethyl5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate withother compounds of formula (13), the following compounds of formula (14)were prepared:

-   (5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol;-   (5-phenyl-4,5-dihydroisoxazol-3-yl)methanol;-   (5-(2,4,6-trimethylphenyl)-4,5-dihydroisoxazol-3-yl)methanol;-   (5-(2,6-dimethylphenyl)-4,5-dihydroisoxazol-3-yl)methanol; and-   (5-(2-chlorophenyl)-4,5-dihydroisoxazol-3-yl)methanol.    C. Preparation of a Compound of Formula (14), Varying X¹

Similarly, following the procedure of 10A above, but replacing ethyl5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate withother compounds of formula (13), other compounds of formula (14) areprepared.

EXAMPLE 11 Preparation of a Chloromethyl Derivative of a Compound ofFormula (14)

A. Preparation of3-(Chloromethyl)-5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole

To a stirred mixture of(5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol (245mg, 1.0 mmol) in methylene chloride (15 mL) was added thionyl chloride(200 μL, 2.74 mmol) dropwise at 0° C. The resulting mixture was stirredunder an atmosphere of nitrogen for 15 hours, concentrated under reducedpressure, and purified by preparative chromatography (3:7 EtOAc:hexane)to yield3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (56mg, M+1=264.1).

B. Preparation of Similar Compounds

Similarly, following the procedure of 11A above, but replacing(5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol withother compounds of formula (14), the following chloromethyl derivativeswere prepared:

-   3-(chloromethyl)-5-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole;-   3-(chloromethyl)-5-phenyl-4,5-dihydroisoxazole;-   3-(chloromethyl)-5-(2,4,6-trimethylphenyl)-4,5-dihydroisoxazole;-   3-(chloromethyl)-5-(2,6-dimethylphenyl)-4,5-dihydroisoxazole; and-   3-(chloromethyl)-5-(2-chlorophenyl)-4,5-dihydroisoxazole.    C. Preparation of Similar Compounds

Similarly, following the procedure of 11A above, but replacing(5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol withother compounds of formula (14), other chloromethyl derivatives areprepared.

EXAMPLE 12 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X¹—Y— is5-(4-trifluoromethylphenyl)-4,5-dihydroisoxazolin-3-yl, X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

To a stirred mixture of(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (30 mg,0.08 mmol) in tert-amylalcohol (5 mL) was added triethylamine (40 μL,0.30 mmol), followed by3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (20mg, 0.08 mmol). The resulting mixture was stirred at 95° C. for 12hours, concentrated under reduced pressure, and purified by preparativechromatograph (1:19 MeOH:CH₂Cl₂) to afford(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol(10 mg, M+1=535.1).

B. Preparation of a Compound of Formula I

Similarly, following the procedure of 12A above, but optionallyreplacing (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-olwith other compounds of formula (6), and optionally replacing3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole withother chloromethyl derivatives, the following compounds of Formula Iwere prepared:

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{[5-(2,4,6-trimethylphenyl)(4,5-dihydroisoxazol-3-yl)]methyl}piperazinyl)propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{[5-(2,6-dimethylphenyl)(4,5-dihydroisoxazol-3-yl)]methyl}piperazinyl)propan-2-ol;

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;and

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[2-chlorophenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol.

C. Preparation of a Compound of Formula I

Similarly, following the procedure of 12A above, but optionallyreplacing (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-olwith other compounds of formula (6), and optionally replacing3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole withother chloromethyl derivatives, other compounds of Formula I areprepared.

EXAMPLE 13 Preparation of a Compound of Formula (15)

A. Preparation of a Compound of Formula (15) in which R¹, R², R³, R⁴,R⁵, R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

To a solution of(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-yl-propan-2-ol (300mg, 1.0 mmol) in acetone (10 ml) was added allyl bromide (0.130 ml, 1.5mmol) and potasium carbonate (280 mg, 2.0 mmol). The solution was heatedto reflux and stirred for 5 hours. Thin layer chromatography (10:1dichloromethane:methanol) showed formation of product. The solution wascooled and filtered. The filtrate was concentrated under reducedpressure, and the residue purified by preparative chromatography (10:1dichloromethane:methanol) to yield(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-enylpiperazinyl)propan-2-ol(150 mg, M+1=348.2)

B. Preparation of a Compound of Formula (15)

Similarly, following the procedure of 13A above, but optionallyreplacing(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-yl-propan-2-ol withother compounds of formula (6), other compounds of formula (15) areprepared as racemates or single enantiomers.

EXAMPLE 14 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I in which R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X¹—Y— is3-(4-Methylphenyl-4,5-dihydroisoxazol-5-yl), X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

To a solution of (hydroxyimino)(4-methylphenyl)methane (97 mg, 0.72mmol) in 1 ml of dichloromethane was added aqueous sodium hypochloritesolution (>4%, 1.33 ml, 0.72 mmol). The reaction mixture was stirred atroom temperature for 30 minutes, after which time TLC (20:1dichloromethane:methanol) showed conversion of oxime to chlorinatedoxime (17).1-(2-Methylbenzothiazol-5-yloxy)-3-(4-prop-2-enylpiperazinyl)propan-2-ol(50 mg, 0.144 mmol) in 0.5 ml of dichloromethane and triethylamine(0.022 ml, 0.145 mmol) were added. The reaction was stirred at roomtemperature overnight. Thin layer chromatography (10:1dichloromethane:methanol) showed consumption of starting material andproduct formation. The solution was evaporated under reduced pressure,and the residue purified by preperative HPLC, to yield(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-{[3-(4-methylphenyl)(4,5-dihydroisoxazol-5-yl)]methyl}piperazinyl)propan-2-ol(3.6 mg, M+1=481.35)

Preparation of Starting Oxime

To a solution of 4-tolualdehyde (600 mg, 5 mmol) in tetrahydrofuran (3ml) was added hydroxylamine hydrochloride (700 mg, 10 mmol) andtriethylamine (1.4 ml, 10 mmol). The reaction was subjected tomicrowave; absorbance normal; temp: 150° C.; time; 600 (s). The solidmaterial was filtered off, and solvent removed from the filtrate underreduced pressure. The residue was purified using column chromatography(2:1 Hexanes:Ethyl Acetate) to provide(hydroxyimino)(4-methylphenyl)methane (500 mg).

EXAMPLE 15 Preparation of a Compound of Formula (6) in which R¹, R², R³,R⁴, R⁵ R⁶ and R⁷ are Hydrogen, R⁸ is (S)-Methyl, T is Oxygen, X² is2-Methylbenzothiazol-5-yl, and Z² is Methylene

To a stirred solution of (2S)-methylpiperazine (1.0 g, 10.0 mmol) inethanol (10 mL) was added slowly a solution of5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (2.20 g, 10.0 mmol)in ethanol (10 mL). The resulting mixture was stirred at 80° C. under anatmosphere of nitrogen for 5 hours. It was then cooled, concentrated,and purified by chromatography (1:9 MeOH:CH₂Cl₂) to yield(2R)-3-((3S)-3-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol(2.28 g, M+1=322.25), which was then treated with 4N HCl in 1,4-dioxane(4 mL, 8.0 mmol) followed by evaporation in vacuum to afford thehydrochloride salt as a pale yellow solid (2.80 g, 7.6 mmol).

EXAMPLE 16 Alternative Preparation of a Compound of Formula IPreparation of a Compound of Formula I in which R¹, R², R³, R⁴, R⁵ R⁶and R⁷ are Hydrogen, R⁸ is (S)-Methyl, T is Oxygen, X¹—Y— is5-(4-Trifluorophenyl-4,5-dihydroisoxazol-3-yl, X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

To a stirred mixture of(2R)-3-((3S)-3-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol(32 mg, 0.08 mmol) in tert-amylalcohol (5 mL) was added triethylamine(42 μL, 0.30 mmol), and 3-chloromethyl-5-(4-trifluorophenyl)isoxazole(20 mg, 0.08 mmol). The resulting mixture was stirred at 95° C. for 12hours. The reaction mixture was then cooled, concentrated under reducedpressure, and purified by preparative chromatograph (1:19 MeOH:CH₂Cl₂)to afford(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol(12 mg, M+1=549.1).

B. Preparation of a Compound of Formula I

Similarly, following the procedure of 16A above, but optionallyreplacing(2R)-3-((3S)-3-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-olwith other compounds of formula (6), and optionally replacing3-chloromethyl-5-(4-trifluorophenyl)isoxazole with other compounds offormula (7), the following compounds of Formula I were prepared:

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(2S)-2-methylpiperazinyl]-3-benzothiazol-5-yloxypropan-2-ol;

(2R)-1-{(3S)-4-[((4S)-2-phenyl(1,3-oxazolin-4-yl))methyl]-3-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](2S)-2-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-{(2S)-4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]-2-methylpiperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](3S)-3-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

N-{[3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](2S)-2-methylpiperazinyl}carbonyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2-chlorophenyl)carboxamide;

3-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl](2R)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl](2R)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-((2S)-2-methyl-4-{[3-(4-methylphenyl)(4,5-dihydroisoxazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-(4-{[3-(4-chlorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-2-methylpiperazinyl)(2R)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{(2S)-2-methyl-4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-{(3S)-3-methyl-4-[(5-phenyl(4,5-dihydroisoxazol-3-yl))methyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-((3S)-4-{[5-(2,6-dimethylphenyl)(4,5-dihydroisoxazol-3-yl)]methyl}-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(3S)-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(2S)-2-methylpiperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(3S)-3-methylpiperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;and

(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)(3S)-3-methylpiperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

C. Preparation of a Compound of Formula I

Similarly, following the procedure of 16A above, but optionallyreplacing(2R)-3-((3S)-3-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-olwith other compounds of formula (6), and optionally replacing3-chloromethyl-5-(4-trifluorophenyl)isoxazole with other compounds offormula (7), other compounds of Formula I are prepared.

EXAMPLE 17 Alternative Preparation of a Compound of Formula IPreparation of a Compound of Formula I in which R¹, R², R³, R⁴, R⁵, R⁶and R⁷ are Hydrogen, R⁸ is (S)-Methyl, T is Oxygen, X¹—Y— is2-Methyl-5-phenyl-4,5-dihydro-oxazol-4-yl, X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

A. To a stirred mixture of((5S)-2-methyl-5-phenyl-1,3-oxazolin-4-yl)methan-1-ol (1.0 mg, 5.23mmol) in methylene chloride (15 mL) was added thionyl chloride (570 μL,7.81 mmol) dropwise at 0° C. The resulting mixture was stirred under anatmosphere of nitrogen for 8 hours, then concentrated under a reducedpressure to afford(5S)-4-chloromethyl-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazole as a whitesolid (960 mg, M+1=210.1).B. To a stirred mixture of(2R)-3-((2S)-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol(51 mg, 0.13 mmol) in tert-amylalcohol (5 mL) was added triethylamine(90 μL, 0.65 mmol), followed by(5S)-4-chloromethyl-2-methyl-5-phenyl-1,3-oxazole (29 mg, 0.14 mmol).The resulting mixture was stirred at 95° C. for 12 hours, concentrated,and purified by preparative chromatograph (1:19 MeOH:CH₂Cl₂) to afford(2R)-3-{(2S)-4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]-2-methylpiperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;(5 mg, M+1=495.2).B. Preparation of a Compound of Formula I

Similarly, following the procedure of 17A and 17B above, but optionallyreplacing ((5S)-2-methyl-5-phenyl-1,3-oxazolin-4-yl)methan-1-ol withother compounds of formula (10), and optionally replacing(2R)-3-((2S)-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-olwith other compounds of formula (6), the following compounds of FormulaI were prepared:

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[2-chlorophenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol;

3-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl](2R)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl](2R)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-(4-{[2-(4-fluorophenyl)(1,3-oxazolin-4-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

(2R)-3-((2S)-2-methyl-4-{[3-(4-methylphenyl)(4,5-dihydroisoxazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-(4-{[3-(4-chlorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-2-methylpiperazinyl)(2R)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol

(2R)-3-{4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]piperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;and

(2R)-3-{(2S)-4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]-2-methylpiperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

EXAMPLE 18 Preparation of a Compound of Formula (22) Preparation of aCompound of Formula (22) in which X¹ is 4-Fluorophenyl

To a cooled (0° C.) solution of allyl alcohol (1.0 ml, 14.7 mmol) inchloroform (15.0 ml) was added 1.0 M diethylzinc in heptane (15.0 ml,15.0 mmol) and stirred for 15 min under an atmosphere of nitrogen. Asolution of (2R,3R)-diisopropyl 2,3-dihydroxysuccinate (2.7 ml, 12.7mmol) was added to above mixture and stirred for 2 hours. Then anotherportion of 1.0 M diethylzinc in heptane (15.0 ml, 15.0 mmol) was addedat 0° C. A solution of α-chloro-4-fluorobenzaldoxime (2.8 g, 16.1 mmol)in chloroform (15 ml) was added to the reaction mixture. After 3 hours,the reaction was quenched with saturated NH₄Cl₄, and the mixtureextracted with CHCl₃ (3×50 ml). The combined organic phase was washedwith brine, dried over Mg₂SO₄, filtered, and concentrated under reducedpressure to yield a crude solid. Chromatography (1:98 to 10:90MeOH:CH₂Cl₂) over silica gel yielded((R)-3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methanol, a compound offormula (22) as a white solid (2.34 g, 12.0 mmol).

EXAMPLE 19 Preparation of(5R)-5-(chloromethyl)-3-(4-fluorophenyl)-4.5-dihydroisoxazole

Thionyl chloride (1.0 M in CH₂Cl₂, 6.0 ml, 6.0 mmol) was added dropwiseto a solution of((R)-3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methanol (1.1 g, 5.6mmol) in methylene chloride (10 ml) at 0° C. for 1 hour. Then thereaction mixture was allowed to warm to room temperature over 6 hours.The product was isolated and purified by removal of solvent underreduced pressure, followed by preparative chromatography (1:9MeOH:CH₂Cl₂) to yield(5R)-5-(chloromethyl)-3-(4-fluorophenyl)-4,5-dihydroisoxazole (1.0 g,4.8 mmol) as a colorless oil.

EXAMPLE 20 Alternative Preparation of a Compound of Formula IPreparation of a Compound of Formula I in which R¹, R², R³, R⁴, R⁵ R⁶and R⁷ are Hydrogen, R⁸ is (S)-Methyl, T is Oxygen, X¹—Y— is3-(4-Fluorophenyl)-4,5-dihydro-oxazol-5-yl, X² is2-Methylbenzothiazol-5-yl, and Z¹ and Z² are Methylene

To a mixture of(2R)-3-((2S)-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol(6.5 mg, 0.02 mmol), and(R)-5-(chloromethyl)-3-(4-fluorophenyl)-4,5-dihydroisoxazole (4.5 mg,0.02 mmol) in tert-amyl alcohol (5.0 ml) was added triethylamine (5 μl,0.04 mmol). The resulting reaction mixture was heated to reflux at 100°C. overnight. After 16 hours the solvent was removed under reducedpressure, and purified by a gradient reverse phase HPLC (acetonitrileand water as eluting solvent) to yield, after concentration (in vacuo)(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol(2.0 mg, 0.004 mmol) as a pale yellow solid.

The following examples illustrate the preparation of representativepharmaceutical formulations containing a compound of Formula I, such asthose prepared in accordance with Examples 8 and 12.

EXAMPLE 21

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 22

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

EXAMPLE 23

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

EXAMPLE 24

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone  4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch  4.5 mg Magnesiumstearate  0.5 mg Talc  1.0 mg Total  120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 25

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 26

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum  4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to  5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

EXAMPLE 27

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 28

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP  50 mg/mlGluconic acid, USP q.s. (pH 5–6) water (distilled, sterile) q.s. to 1.0ml Nitrogen Gas, NF q.s.

EXAMPLE 29

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2–10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

EXAMPLE 30

Sustained Release Composition Weight Preferred Ingredient Range (%)Range (%) Most Preferred Active ingredient 50–95 70–90 75Microcrystalline cellulose (filler)  1–35  5–15 10.6 Methacrylic acidcopolymer  1–35   5–12.5 10.0 Sodium hydroxide 0.1–1.0 0.2–0.6 0.4Hydroxypropyl methylcellulose 0.5–5.0 1–3 2.0 Magnesium stearate 0.5–5.01–3 2.0

The sustained release formulations of this invention are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed(dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400–600 mg, 650–850 mg, and900–1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

EXAMPLE 31 Mitochondrial Assays

Rat heart mitochondria were isolated by the method of Nedergard andCannon (Methods in Enzymol. 55, 3, 1979).

Palmitoyl CoA oxidation—The Palmityl CoA oxidation was carried out in atotal volume of 100 micro liters containing the following agents: 110 mMKCl, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl₂, 0.1 mM EDTA, 14.7microM defatted BSA, 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52micrograms of mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA(Sp. Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters perassay). The compounds of this invention were added in a DMSO solution atthe following concentrations: 100 micro molar, 30 micro molar, and 3micro molar. In each assay, a DMSO control was used. After 15 min at 30°C., the enzymatic reaction was centrifuged (20,000 g for 1 min), and 70microliters of the supernatant was added to an activated reverse phasesilicic acid column (approximately 0.5 ml of silicic acid). The columnwas eluted with 2 ml of water, and 0.5 ml of the eluent was used forscintillation counting to determine the amount of C¹⁴ trapped as C¹⁴bicarbonate ion.

The compounds of the invention showed activity as fatty acid oxidationinhibitors in this assay. Representative examples of test data is shownbelow, along with the NMR determined for the compound.

(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol

1HNMR (400 MHz CD3OD) d 7.95 (d, J=9.00 Hz, 1H, H5), 7.73 (d, J=8.22 Hz,2H, H20), 7.61 (d, J=8.22 Hz, 2H, H19), 7.52 (d, J=2.35 Hz, 1H, H8),7.26 (dd, J=2.74, 9.00 Hz, 1H, H6), 5.82 (dd, J=8.22, 11.4 Hz, 1H, H17),4.53 (m, 1H, H10), 4.18 (d, J=4.70 Hz, 2H, H9), 3.91 (s, 2H, H14),3.47–3.76 (m, 6H, H11, H12, H12′, H13, H13′), 3.12 (m, 2H, H16), 2.97(s, 3H, H1); MS: m/z 535 (100, MH+). EC50=1.70 mMa, Liver S-9 index:1.00b

(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol

1HNMR (400 MHz CD3OD) d 7.74 (m, 1H, H5), 7.65 (m, 2H, H20), 7.52 (m,2H, H19), 7.40 (m,1H, H8), 7.06 (m, 1H, H6), 5.67 (m, 1H, H17), 4.13 (m,1H, H10), 4.05 (m, 2H, H9), 2.82–3.63 and 2.30–2.70 (m, 11H, H14, H11,H12, H12′, H13, H13′), 2.78 (s, 3H, H1), 2.05 (m, 2H, H16), 1.08 (d, 3H,H23); MS: m/z 549 (100, MH+). EC50=0.24 mMa, Liver S-9 index: 0.39b

(2R)-1-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol

1HNMR (400 MHz CD3OD) d 7.70 (d, J=9.00 Hz, 1H, H5), 7.75 (d, J=8.23 Hz,2H, H20), 7.64 (d, J=8.23 Hz, 2H, H19), 7.44 (d, J=2.33 Hz, 1H, H8),7.20 (dd, J=2.73, 9.00 Hz, 1H, H6), 5.69 (dd, J=8.18, 10.9 Hz, 1H, H17),4.44 (m, 1H, H10), 4.14 (d, J=4.72 Hz, 2H, H9), 3.83 (s, 2H, H14),3.40–3.71 (m, 6H, H11, H12, H12′, H13, H13′), 3.08 (m, 2H, H16), 2.91(s, 3H, H1); 1.28 (d, 3H, H23); MS: m/z 549 (100, MH+). EC50=0.14 mMa,Liver S-9 index: NA

(2R)-1-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol

1HNMR (400 MHz CD3OD) d 7.87 (m, 1H, H5), 7.70 (m, 2H, H20), 7.55 (m,2H, H19), 7.41 (m, 1H, H8), 7.08 (m, 1H, H6), 5.60 (m, 1H, H17), 4.16(m, 1H, H10), 4.08 (m, 2H, H9), 2.78–3.60 and 2.28–2.67 (m, 11H, H14,H11, H12, H12′, H13, H13′), 2.72 (s, 3H, H1), 2.00 (m, 2H, H16), 1.13(d, 3H, H23); MS: m/z 549 (100, MH+). EC50=0.17 mMa, Liver S-9 index:0.03b.

(2R)-1-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol

1HNMR (400 MHz CD3OD) d 7.72 (m, 1H, H5), 7.58 (m, 3H, H19, H20, H20′),7.47 (t, J=7.83 Hz, 1H, H21), 7.38 (m, 1H, H8), 7.10 (m, 1H, H6), 5.63(m, 1H, H17), 4.49 (m, 1H, H10), 4.17 (m, 2H, H9), 3.84 (s, 2H, H14),3.42–3.75 (m, 6H, H11, H12, H12′, H13, H13′), 3.09 (m, 2H, H16), 2.87(s, 3H, H1); 1.20 (d, 3H, H23); MS: m/z 549 (100, MH+). EC50=0.40 mMa,Liver S-9 index: NA

(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol

1HNMR (400 MHz CD3OD) d 7.91 (d, J=9.00 Hz, 1H, H5), 7.68 (m, 3H, H19,H20, H20′), 7.51 (t, J=7.80 Hz, 1H, H21), 7.47 (d, J=2.34 Hz, 1H, H8),7.21 (dd, J=2.74, 9.00 Hz, 1H, H6), 6.01 (dd, J=8.61, 10.28 Hz, 1H,H17), 4.50 (m, 1H, H10), 4.14 (d, J=4.70 Hz, 2H, H9), 3.84 (s, 2H, H14),3.42–3.74 (m, 6H, H11, H12, H12′, H13, H13′), 3.00 (m, 2H, H16), 2.92(s, 3H, H1); MS: m/z 535 (100, MH+). EC50=1.74 mMa, Liver S-9 index: NA

(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol

1HNMR (400 MHz CD3OD) d 7.98 (d, J=9.00 Hz, 1H, H5), 7.70 (m, 3H, H19,H20, H20′), 7.53 (t, J=7.93 Hz, 1H, H21), 7.50 (d, J=2.36 Hz, 1H, H8),7.23 (dd, J=2.74, 9.00 Hz, 1H, H6), 4.52 (m, 1H, H10), 4.18 (d, J=4.69Hz, 2H, H9), 3.90 (m, 1H, H15), 3.83 (s, 2H, H14), 3.35–3.70 (m, 6H,H11, H12, H12′, H13, H13′), 2.97 (m, 2H, H16), 2.90 (s, 3H, H1); MS: m/z535 (100, MH+).

IC50 values are the mean of n=3, experiments were carried out at 6different concentrations. Each experiment was carried out in triplicate.Experiments were carried out using human liver S-9.

EXAMPLE 32

Perfusate

Langendorff perfusion is conducted using a Krebs-Henseleit solutioncontaining: (mM) NaCl (118.0), KCl (4.7), KH₂PO₄ (1.2), MgSO₄ (1.2),CaCl₂ (2.5), NaHCO₃ (25.0) and glucose (5.5 or 11) (Finegan et al.1996). The working heart perfusate consists of a Krebs-Henseleitsolution with the addition of palmitate (0.4 or 1.2 mM) pre-bound to 3%bovine serum albumin (essentially fatty acid free BSA) and insulin (100μU/ml). Palmitate is initially dissolved in an ethanol:water mixture(40%:60%) containing 0.5–0.6 g Na₂CO₃ per g of palmitate. Followingheating to evaporate the ethanol, this mixture is then added to the 3%BSA-Krebs-Henseleit mixture (without glucose) and allowed to dialyze(8000 MW cut-off) overnight in 10 volumes of glucose-freeKrebs-Henseleit solution. The next day, glucose is added to the solutionand the mixture was filtered through glass microfiber filters (GF/C,Whatman, Maidstone, England) and kept on ice, or refrigerated, prior touse. The perfusate is continuously oxygenated with a 95% CO₂, 5% O₂ gasmixture while in the perfusion apparatus to main aerobic conditions.

EXAMPLE 33

Heart Perfusion Protocols

Rats are anesthetized with pentobarbital (60 mg/kg, intraperitoneally)and hearts rapidly removed and placed in ice-cold Krebs-Henseleitsolution. The hearts are then rapidly cannulated via the aortic stumpand Langendorff perfusion at constant pressure (60 mm Hg) is initiatedand continued for a 10-min equilibration period. During thisequilibration period, the pulmonary artery is cut, and excess fat andlung tissue removed to reveal the pulmonary vein. The left atrium iscannulated and connected to the preload line originating from theoxygenation chamber. After the 10-min equilibration period, hearts areswitched to working mode (by clamping off the Langendorff line andopening the preload and afterload lines) and perfused at 37° C. underaerobic conditions at a constant left atrial preload (11.5 mm Hg) andaortic afterload (80 mm Hg). The compliance chamber is filled with airadequate to maintain developed pressure at 50–60 mm Hg. Perfusate isdelivered to the oxygenation chamber via a peristaltic pump from thereservoir chamber that collected aortic and coronary flows as well asoverflow from the oxygenator.

Typically, hearts are perfused under aerobic conditions for 60 min.Hearts are paced at 300 beats/min throughout each phase of the perfusionprotocol (voltage adjusted as necessary) with the exception of theinitial 5 min of reperfusion when hearts are allowed to beatspontaneously.

At the end of the perfusion protocol, hearts are rapidly frozen usingWollenberger clamps cooled to the temperature of liquid nitrogen. Frozentissues are pulverized and the resulting powders stored at −80° C.

EXAMPLE 34

Myocardial Mechanical Function

Aortic systolic and diastolic pressures are measured using a Sensonor(Horten Norway) pressure transducer attached to the aortic outflow lineand connected to an AD Instruments data acquisition system. Cardiacoutput, aortic flow and coronary flow (cardiac output minus aortic flow)are measured (ml/min) using in-line ultrasonic flow probes connected toa Transonic T206 ultrasonic flow meter. Left ventricular minute work (LVwork), calculated as cardiac output×left ventricular developed pressure(aortic systolic pressure−preload pressure), is used as a continuousindex of mechanical function. Hearts are excluded if LV work decreasedmore than 20% during the 60-min period of aerobic perfusion.

EXAMPLE 35

Myocardial Oxygen Consumption and Cardiac Efficiency

Measuring the atrial-venous difference in oxygen content of theperfusate and multiplying by the cardiac output provides an index ofoxygen consumption. Atrial oxygen content (mmHg) is measured inperfusate in the preload line or just prior to entering the left atria.Venous oxygen content is measured from perfusate exiting the pulmonaryartery and passing through in-line O₂ probes and meters MicroelectrodesInc., Bedford, N.H. Cardiac efficiency is calculated as the cardiac workper oxygen consumption.

EXAMPLE 36

Measurement of Glucose and Fatty Acid Metabolism

Determining the rate of production of ³H₂O and ¹⁴CO₂ from[³H/¹⁴C]glucose in the isolated working rat model allows a direct andcontinuous measure of the rates of glycolysis and glucose oxidation.Alternatively, the measure of the production of ³H₂O from[5-³H]palmitate provides a direct and continuous measure of the rate ofpalmitate oxidation. Dual labelled substrates allows for thesimultaneous measure of either glycolysis and glucose oxidation or fattyacid oxidation and glucose oxidation. A 3-ml sample of perfusate istaken from the injection port of the recirculating perfusion apparatusat various time-points throughout the protocol for analysis of ³H₂O and¹⁴CO₂ and immediately placed under mineral oil until assayed formetabolic product accumulation. Perfusate is supplemented with[³H/¹⁴C]glucose or [5-³H]palmitate to approximate a specific activity of20 dpm/mmol. Average rates of glycolysis and glucose oxidation arecalculated from linear cumulative time-courses of product accumulationbetween 15 and 60 min for aerobic perfusion. Rates of glycolysis andglucose oxidation are expressed as μmol glucose metabolized/min/g drywt.

EXAMPLE 37

Measurement of Myocardial Glycolysis

Rates of glycolysis are measured directly as previously described(Saddik & Lopaschuk, 1991) from the quantitative determination of ³H₂Oliberated from radiolabeled [5-³H]glucose at the enolase step ofglycolysis. Perfusate samples are collected at various time-pointsthroughout the perfusion protocol. ³H₂O is separated from the perfusateby passing perfusate samples through columns containing Dowex 1-X 4anion exchange resin (200–400 mesh). A 90 g/L Dowex in 0.4 M potassiumtetraborate mixture is stirred overnight after which 2 ml of thesuspension is loaded into separation columns and washed extensively withdH₂O to remove the tetraborate. The columns are found to exclude98–99.6% of the total [³H]glucose (Saddik & Lopaschuk, 1996). Perfusatesamples (100 μl) are loaded onto the columns and washed with 1.0 mldH₂O. Effluent is collected into 5 ml of Ecolite Scintillation Fluid(ICN, Radiochemicals, Irvine, Calif.) and counted for 5 min in a BeckmanLS 6500 Scintillation Counter with an automatic dual (³H/¹⁴C) quenchcorrection program. Average rates of glycolysis for each phase ofperfusion are expressed as μmol glucose metabolized/min/g dry wt asdescribed above.

EXAMPLE 38

Measurement of Myocardial Glucose Oxidation

Glucose oxidation is also determined directly as previously described(Saddik & Lopaschuk, 1991) by measuring ¹⁴CO₂ from [¹⁴C]glucoseliberated at the level of pyruvate dehydrogenase and in the Krebs cycle.Both ¹⁴CO₂ gas exiting the oxygenation chamber and [¹⁴C]bicarbonateretained in solution are measured. Perfusate samples are collected atvarious time-points throughout the perfusion protocol. ¹⁴CO₂ gas iscollected by passing the gas exiting the oxygenator through a hyaminehydroxide trap (20–50 ml depending on perfusion duration). Perfusatesamples (2×1 ml), which are stored under oil to prevent the escape ofgas by equilibration with atmospheric CO₂, are injected into 16×150 mmtest tubes containing 1 ml of 9 N H₂SO₄. This process releases ¹⁴CO₂from the perfusate present as H¹⁴CO₃ ⁻. These duplicate tubes are sealedwith a rubber stopper attached to a 7-ml scintillation vial containing a2×5 cm piece of filter paper saturated with 250 □l of hyamine hydroxide.The scintillation vials with filter papers are then removed and EcoliteScintillation Fluid (7 ml) added. Samples are counted by standardprocedures as described above. Average rates of glucose oxidation foreach phase of perfusion are expressed as μmol glucose metabolized/min/gdry wt as described above.

EXAMPLE 39

Measurement of Myocardial Fatty Acid Oxidation

Rates of palmitate oxidation are measured directly as previouslydescribed (Saddik & Lopaschuk, 1991) from the quantitative determinationof ³H⁻H₂O liberated from radiolabeled [5-³H]palmitate. ³H₂O is separatedfrom [5-³H]palmitate following a chloroform:methanol (1.88 ml of 1:2v/v) extraction of a 0.5 ml sample of buffer then adding 0.625 ml ofchloroform and 0.625 ml of a 2M KCL:HCl solution. The aqueous phase isremoved and treated with a mixture of chloroform, methanol and KCl:HCl(1:1:0.9 v/v). Duplicate samples are taken from the aqueous phase forliquid scintillation counting and rates of oxidation are determinedtaking into account a dilution factor. This results in >99% extractionand separation of ³H₂O from [5-³H]palmitate. Average rates of glucoseoxidation for each phase of perfusion are expressed as μmol glucosemetabolized/min/g dry wt as described above.

Dry to Wet Ratios

Frozen ventricles are pulverized at the temperature of liquid nitrogenwith a mortar and pestle. Dry to wet determinations are made by weighinga small amount of frozen heart tissue and re-weighing that same tissueafter 24–48 hr of air drying and taking the ratio of the two weights.From this ratio, total dry tissue can be calculated. This ratio is usedto normalize, on a per g dry weight basis, rates of glycolysis, glucoseoxidation and glycogen turnover as well as metabolite contents.

The compounds of the invention show activity as fatty acid oxidationinhibitors in this assay.

References

-   1. Finegan B A, Gandhi M, Lopaschuk G D, Clanachan A S, 1996.    Antecedent ischemia reverses effects of adenosine on glycolysis and    mechanical function of working hearts. American Journal of    Physiology 271: H2116–25.-   2. Saddik M, Lopaschuk G D, 1991. Myocardial triglyceride turnover    and contribution to energy substrate utilization in isolated working    rat hearts. Journal of Biological Chemistry 266: 8162–8170.

While the present invention has been described with reference to thespecific embodiments thereof, it will be understood by those skilled inthe art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. All patents and publications cited above arehereby incorporated by reference.

1. A compound of Formula I: wherein:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen, lower alkyl, or —C(O)R;in which R is —OR⁹ or —NR⁹R¹⁰, where R⁹ and R¹⁰ are hydrogen or loweralkyl; or R¹ and R², R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, when takentogether with the carbon to which they are attached, represent carbonyl;or R¹ and R⁵, or R¹ and R⁷, or R³ and R⁵, or R³ and R⁷, when takentogether form a bridging group —(CR¹²R¹³)_(n)—, in which n is 1, 2 or 3,and R¹² and R¹³ are independently hydrogen or lower alkyl; with theproviso that (a) the maximum number of carbonyl groups is 1; (b) themaximum number of —C(O)NR⁹R¹⁰ groups is 1; and (c) the maximum number ofbridging groups is 1; T is oxygen, sulfur, or NR¹¹, in which R¹¹ ishydrogen or lower alkyl; V is —N<; X¹ is hydrogen, optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; X² is optionallysubstituted aryl or optionally substituted heteroaryl; Y is optionallysubstituted dihydroheteroaryl; and Z¹ and Z² are independentlyoptionally substituted alkylene of 1–4 carbon atoms.
 2. A compound ofclaim 1, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independentlychosen from hydrogen and methyl.
 3. A compound of claim 2, wherein X¹ isoptionally substituted aryl and X² is optionally substituted heteroaryl.4. The compound of claim 3, wherein Z¹ is methylene and Z² is methyleneor ethylene.
 5. The compound of claim 4, wherein Y is optionallysubstituted dihydroheteroaryl in which the hetero atoms are chosen fromnitrogen and oxygen.
 6. The compound of claim 5, wherein T is oxygen, X¹is optionally substituted phenyl, and Y is optionally substitutedisoxazolyl.
 7. The compound of claim 6, wherein X² is optionallysubstituted benzothiazolyl.
 8. The compound of claim 7, wherein Y isoptionally substituted 5-(4,5-dihydroisoxazol-3-yl).
 9. The compound ofclaim 8, wherein X¹ is 4-(trifluoromethyl)phenyl, X² is2-methylbenzothiazol-5-yl, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen, and Z² is methylene, namely1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol.10. The compound of claim 9, namely(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol.11. The compound of claim 8, wherein X¹ is 2-(trifluoromethyl)phenyl, X²is 2-methylbenzothiazol-5-yl; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen, and Z² is methylene, namely3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol.12. The compound of claim 11, namely(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol.13. The compound of claim 8, wherein X¹ is 4-(trifluoromethyl)phenyl, X²is 2-methylbenzothiazol-5-yl, R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen, R³ is (S)-methyl, and Z² is methylene, namely1-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.14. The compound of claim 13, namely(2R)-1-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.15. The compound of claim 8, wherein X¹ is 2-(trifluoromethyl)phenyl, X²is 2-methylbenzothiazol-5-yl, R¹, R³, R², R⁴, R⁵, R⁶, and R⁸ arehydrogen, R⁷ is (S)-methyl, and Z² is methylene, namely1-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.16. The compound of claim 15, namely(2R)-1-[(3S)-3-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.17. The compound of claim 8, wherein X¹ is 4-(trifluoromethyl)phenyl, X²is 2-methylbenzothiazol-5-yl, R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ arehydrogen, R⁷ is (S)-methyl, and Z² is methylene, namely3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.18. The compound of claim 17, namely(2R)-3-[(3S)-3-methyl-4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.19. The compound of claim 8, wherein X¹ is 2-(trifluoromethyl)phenyl, X²is 2-methylbenzothiazol-5-yl, R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen, R³ is (S)-methyl, and Z² is methylene, namely1-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.20. The compound of claim 19, namely(2R)-1-[(2S)-2-methyl-4-({5-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.21. The compound of claim 7, wherein Y is optionally substituted3-(4,5-dihydroisoxazol-5-yl).
 22. The compound of claim 21, wherein X¹is 4-(trifluoromethyl)phenyl, X² is 2-methylbenzothiazol-5-yl, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen, and Z² is methylene, namely1-[4-({3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.23. The compound of claim 22, namely(2R)-1-[4-({(5R)-3-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.24. The compound of claim 21, wherein X¹ is 2-(trifluoromethyl)phenyl,X² is 2-methylbenzothiazol-5-yl, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ arehydrogen, and Z² is methylene, namely1-[4-({3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.25. The compound of claim 24, namely(2R)-1-[4-({(5R)-3-[2-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-5-yl)}methyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.26. The compound of claim 21, wherein X¹ is 4-fluorophenyl, X² is2-methylbenzothiazol-5-yl, R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen,R³ is (S)-methyl, and Z² is methylene, namely1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.27. The compound of claim 26, namely(2R)-1-(4-{[(5R)-3-(4-fluorophenyl)(4,5-dihydroisoxazol-5-yl)]methyl}(2S)-3-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.28. The compound of claim 21, wherein X¹ is phenyl, X² is2-methylbenzothiazol-5-yl, R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen,R³ is (S)-methyl, and Z² is methylene, namely1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](2S)-2-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.29. The compound of claim 28, namely(2R)-1-{4-[((5R)-3-phenyl(4,5-dihydroisoxazol-5-yl))methyl](2S)-2-methylpiperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.30. A method of treating a disease state chosen from diabetes, damage toskeletal muscles resulting from trauma or shock and a cardiovasculardisease in a mammal by administration of a therapeutically effectivedose of a compound of claim
 1. 31. The method of claim 30, wherein thecardiovascular disease is atrial arrhythmia, intermittent claudication,ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina,unstable angina, congestive heart disease, or myocardial infarction. 32.The method of claim 30, wherein the disease state is diabetes.
 33. Apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of claim 1.